Cardiovascular disease continues to be the primary cause of morbidity and mortality in North America. The risk of premature atherosclerosis and platelet-dependent cardiovascular events rises with increasing obesity. Complicating this observation is that not all individuals with elevated BMI go on to develop athero-thrombotic disease. We measured expression of 48 genes by high-throughput quantitative reverse transcription PCR in over 2250 participants of the Framingham Offspring and Omni minority cohorts (FHS) using RNA from isolated platelets and found that specific mitochondrial transcripts were significantly and specifically associated with higher body mass index. To determine if there were associated changes in platelet function, we studied select platelet transcripts and function from individuals after short term triglyceride emulsion infusion (acute effect) and identified similar alterations in platelet transcripts that associated with changes in platelet activation. Thus, the central hypothesis of this project is: In the setting of obesity, the human platelet is reprogrammed as seen by altered platelet RNA, including mitochondrial transcripts, and these changes lead to a prothrombotic phenotype that influences the development of athero-thrombotic disease. The effect of obesity on the human platelet as seen in its transcript profile and platelet function will be studied as follows: Aim 1. Characterize the molecular signature of platelets in the setting of increased BMI and determine if it is caused by short term fat intake or chronic obesity and if the changes are reversible with weight loss. Aim 2. Determine the mechanism by which platelet reprogramming alters platelet function including the role of the mitochondria. Aim 3. Determine if platelet reprogramming correlates with subclinical cardiovascular disease (CVD) and the development of clinical CVD. This information along with transcripts from Projects 1-3 and proteins screened in Aim 1 will establish a biomarker panel identifying individuals with elevated BMI at high risk for athero-thrombotic disease. This project seeks not only to define the mechanism by which platelet reprogramming alters function but will determine the human relevance and develop a transcript-based profile.